Fig. 2.

Intrinsic cancer cell pathways mediate the regulation of PD-L1 expression and MHC in EGFR-mutant NSCLC. Activation of EGFR may lead to downregulation of MHC expression through the MEK/ERK signaling pathway. In addition, activation of EGFR may influence expression of IFN-γR, generating intracellular signals that induce expression of the CIITA gene. CIITA is recruited to the MHC promoter, activating transcription. The net result is attenuation of CIITA and MHC molecule expression. In response to EGFR-TKIs, expression of CIITA and MHC genes is derepressed. In addition, EGFR-TKIs enhance MHC expression by inhibiting ERK activation. CIITA: class II major histocompatibility complex transactivator; TME: tumor microenvironment; MEK/ERK: extracellular signal–regulated kinase (ERK) kinase MEK; IFN-γR: interferon γ receptor; MHC: major histocompatibility complex; EGFR-TKIs: epidermal growth factor receptor tyrosine kinase inhibitors; EGFR: epidermal growth factor receptor; IFN-γ: interferon-γ